Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue -, Pages 470-482Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.05.036
Keywords
Ionotropic glutamate receptors; 3-Hydroxyquinazoline-2,4-diones; AMPA receptor antagonists; Kainate receptor antagonists; Neuroprotective agents; Ligand-receptor modeling studies
Categories
Funding
- University of Florence
- Italian Ministry for University and Research, Italy
- University of Padova, Italy
- Italian Ministry for University and Research, Rome, Italy
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Based on our 3-hydroxy-7-chloroquinazoline-2,4-dione derivatives, previously reported as antagonists at ionotropic glutamate receptors, we synthesized new 3-hydroxyquinazoline-2,4-diones bearing a trifluoromethyl group at the 7-position and different groups at position 6. Glycine/NMDA, AMPA and kainate receptor binding data showed that the 7-trifluoromethyl residue increased AMPA and kainate receptor affinity and selectivity, with respect to the 7-chlorine atom. Among the probed 6-substituents, the 6-(1,2,4-triazol-4-yl) group (compound 8) was the most advantageous for AMPA receptor affinity and selectivity. Derivative 8 demonstrated to be effective in decreasing neuronal damage produced by oxygen and glucose deprivation in organotypic rat hippocampal slices and also showed anticonvulsant effects in pentylenetetrazole-induced convulsions. The previously reported kainate receptor antagonist 6-(2-carboxybenzoyl)-amino-7-chloro-3-hydroxyquinazoline-2,4-dione 3 prevented the failure of neurotransmission induced by oxygen and glucose deprivation in the CA1 region of rat hippocampal slices. (C) 2012 Elsevier Masson SAS. All rights reserved.
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